1. Field of the Invention
This invention relates generally to humanized anti-CD11a antibodies.
2. Description of Related Art
Lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) is involved in leukocyte adhesion during cellular interactions essential for immunologic responses and inflammation (Larson et al., Immunol. Rev. 114:181-217 (1990)). LFA-1 is a member of the .beta.2 integrin family and consists of a unique .alpha. subunit, CD11a, and a .beta. subunit, CD18, common to other .beta.2 integrin receptors Mac-1 and p150,95. The ligands of LFA-1 include intercellular adhesion molecule-1, .vertline.CAM-1, expressed on leukocytes, endothelium, and dermal fibroblasts (Dustin et al., J. Immunol. 137: 245-254 (1986)), ICAM-2 expressed on resting endothelium and lymphocytes (de Fougerolles et a., J. Exp. Med. 174: 253-267 (1991)), and ICAM-3 expressed on monocytes and resting lymphocytes (de Fougerolles et al., J. Exp. Med. 179: 619-629 (1994)).
Monoclonal antibodies (MAbs) against LFA-1 and the ICAMs have been shown, in vitro, to inhibit several T cell-dependent immune functions including T cell activation (Kuypers et al., Res. Immunol. 140: 461(1989)), T cell-dependent B cell proliferation (Fischer et al., J. Immunol. 136: 3198-3203 (1986)), target cell lysis (Krensky et al., J. Immunol. 131: 611-616 (1983)), and adhesion of T cells to vascular endothelium (Lo et al., J. Immunol. 143: 3325-3329 (1989)). In mice, anti-CD11a MAbs induce tolerance to protein antigens (Tanaka et al., Eur. J. Immunol. 25: 1555-1558 (1995)) and prolong survival of cardiac (Cavazzana-Calvo et al., Transplantation 59: 1576-1582 (1995); Nakakura et al., Transplantation 55: 412-417 (1993)), bone marrow (Cavazzana-Calvo et al., Transplantation 59: 1576-1582 (1995); van Dijken et al., Transplantation 49: 882-886 (1990)), corneal (He et al., Invest. Opthamol. Vis. Sci. 35: 3218-3225 (1994)), islet (Nishihara et al., Transplantation Proc. 27: 372 (1995)) and thyroid (Talento et al., Transplantation 55: 418-422 (1993)) allografts.
In humans, anti-CD11a MAbs prevent graft failure after bone marrow transplantation (Fischer et al., Blood 77: 249-256 (1991); Stoppa et al., Transplant Intl. 4: 3-7 (1991)) and preliminary clinical studies of renal allografts treated prophylactically with anti-CD11a MAb, in addition to corticosteroids and azathioprine, are promising (Hourmant et al., Transplantation 58: 377-380 (1994)). Current therapies against graft rejection include use of OKT3, a murine anti-human CD3 MAb, and cyclosporin A. OKT3 therapy is effective but has several undesirable side effects; its use results in the release of numerous cytokines including tumor necrosis factor-.alpha., interferon-.gamma., interleukin-2, and interleukin-6, resulting in fever, chills and gastrointestinal distress (for a review see Parlevliet et al., Transplant Intl. 5: 234-246 (1992); Dantal et al., Curr. Opin. Immunol. 3: 740-747 (1991)). Cyclosporin A is effective but also has serious side effects (for a review see Barry, Drugs, 44: 554-566 (1992)).